Background
Methods
Study design
Patients
Study endpoints
Statistical analysis
Results
Patient disposition and characteristics
Total | HbA1c, % | P-value* | ||||
---|---|---|---|---|---|---|
< 6.0 (n = 8725) | 6.0 to < 7.0 (n = 6700) | 7.0 to < 8.0 (n = 1548) | ≥ 8.0 (n = 553) | |||
Male | 10,351 (59.1) | 4955 (56.8) | 4111 (61.4) | 981 (63.4) | 304 (55.0) | < 0.001 |
Age (years) | 81.3 ± 4.7 | 81.4 ± 4.8 | 81.1 ± 4.6 | 80.8 ± 4.4 | 81.7 ± 4.6 | < 0.001 |
≥ 85 years | 4336 (24.7) | 2288 (26.2) | 1566 (23.4) | 332 (21.4) | 150 (27.1) | - |
Body mass index (kg/m2) | 23.6 ± 3.6 | 23.2 ± 3.5 | 24.0 ± 3.7 | 24.4 ± 3.6 | 24.3 ± 4.0 | < 0.001 |
Systolic blood pressure (mmHg) | 127.6 ± 16.8 | 127.6 ± 16.7 | 127.3 ± 16.8 | 128.2 ± 16.7 | 128.0 ± 17.8 | 0.297 |
Creatinine clearance (mL/min) | 49.6 ± 18.7 | 49.2 ± 17.4 | 50.3 ± 20.5 | 50.2 ± 17.2 | 47.6 ± 18.6 | < 0.001 |
< 50 mL/min | 8527 (48.7) | 4343 (49.8) | 3137 (46.8) | 745 (48.1) | 302 (54.6) | - |
Hemoglobin (g/dL) | 13.0 ± 1.7 | 12.9 ± 1.7 | 13.0 ± 1.7 | 13.1 ± 1.8 | 13.1 ± 1.9 | < 0.001 |
CHA2DS2-VASc score | 4.6 ± 1.4 | 4.3 ± 1.4 | 4.8 ± 1.4 | 5.3 ± 1.3 | 5.5 ± 1.4 | < 0.001 |
HAS-BLED score | 1.9 ± 0.9 | 1.9 ± 0.9 | 1.9 ± 0.9 | 2.1 ± 0.9 | 2.1 ± 0.9 | < 0.001 |
History of major bleeding | 802 (4.6) | 394 (4.5) | 315 (4.7) | 65 (4.2) | 28 (5.1) | 0.773 |
AF type | ||||||
Paroxysmal | 7097 (40.5) | 3802 (43.6) | 2538 (37.9) | 567 (36.6) | 190 (34.4) | < 0.001 |
Persistent/Long-standing persistent | 5341 (30.5) | 2583 (29.6) | 2062 (30.8) | 520 (33.6) | 176 (31.8) | - |
Permanent | 5088 (29.0) | 2340 (26.8) | 2100 (31.3) | 461 (29.8) | 187 (33.8) | - |
Anticoagulant | 16,264 (92.8) | 8000 (91.7) | 6287 (93.8) | 1458 (94.2) | 519 (93.9) | < 0.001 |
DOAC | 11,921 (68.0) | 6078 (69.7) | 4450 (66.4) | 1048 (67.7) | 345 (62.4) | < 0.001 |
Warfarin | 4336 (24.7) | 1918 (22.0) | 1836 (27.4) | 410 (26.5) | 172 (31.1) | < 0.001 |
TTR | 75.8 ± 29.5 | 75.0 ± 30.1 | 76.8 ± 28.8 | 75.6 ± 30.3 | 74.5 ± 29.4 | 0.342 |
Antidiabetic medication
| ||||||
Oral diabetes medication | 4318 (24.6) | 468 (5.6) | 2277 (35.1) | 1149 (75.1) | 424 (77.4) | < 0.001 |
Sulfonylurea | 1073 (6.1) | 72 (0.9) | 424 (6.5) | 386 (25.2) | 191 (34.9) | < 0.001 |
Alpha-glucosidase inhibitor | 851 (4.9) | 87 (1.0) | 421 (6.5) | 250 (16.3) | 93 (17.0) | < 0.001 |
Thiazolidinedione | 333 (1.9) | 36 (9.4) | 165 (2.5) | 90 (5.9) | 42 (7.7) | < 0.001 |
Dipeptidyl peptidase-4 inhibitor | 3360 (19.2) | 343 (4.1) | 1773 (27.3) | 911 (59.5) | 333 (60.8) | < 0.001 |
Sodium glucose co-transporter 2 inhibitor | 364 (2.1) | 21 (0.3) | 170 (2.6) | 115 (7.5) | 58 (10.6) | < 0.001 |
Others | 874 (5.0) | 50 (0.6) | 443 (6.8) | 286 (18.7) | 95 (17.3) | < 0.001 |
Insulin | 560 (3.2) | 26 (0.3) | 162 (2.5) | 211 (13.8) | 161 (29.4) | < 0.001 |
Glucagon-like peptide-1 receptor agonist | 67 (0.4) | 3 (0.0) | 31 (0.5) | 22 (1.4) | 11 (2.0) | < 0.001 |
Comorbidities
| ||||||
Hypertension | 13,539 (77.3) | 6597 (75.6) | 5273 (78.7) | 1242 (80.2) | 427 (77.2) | < 0.001 |
Diabetes mellitus | 7083 (40.4) | 1259 (14.4) | 3837 (57.3) | 1456 (94.1) | 531 (96.0) | < 0.001 |
Dyslipidemia | 8246 (47.1) | 3502 (40.1) | 3520 (52.5) | 894 (57.8) | 330 (59.7) | < 0.001 |
Chronic kidney disease | 4008 (22.9) | 1892 (21.7) | 1548 (23.1) | 415 (26.8) | 153 (27.7) | < 0.001 |
Cardiac disorders | 10,537 (60.1) | 5012 (57.4) | 4133 (61.7) | 1021 (66.0) | 371 (67.1) | < 0.001 |
Myocardial infarction | 1182 (6.7) | 431 (4.9) | 520 (7.8) | 165 (10.7) | 66 (11.9) | < 0.001 |
Heart failure | 6589 (37.6) | 3123 (35.8) | 2593 (38.7) | 618 (39.9) | 255 (46.1) | < 0.001 |
Cerebrovascular disorders | 4185 (23.9) | 2012 (23.1) | 1618 (24.1) | 408 (26.4) | 147 (26.6) | 0.012 |
Thrombosis and embolism-related diseases | 1691 (9.6) | 741 (8.5) | 707 (10.6) | 180 (11.6) | 63 (11.4) | < 0.001 |
Gastrointestinal disease | 5311 (30.3) | 2648 (30.3) | 2028 (30.3) | 473 (30.6) | 162 (29.3) | 0.955 |
Active cancer | 1913 (10.9) | 862 (9.9) | 790 (11.8) | 193 (12.5) | 68 (12.3) | < 0.001 |
Dementia | 1358 (7.7) | 700 (8.0) | 467 (7.0) | 120 (7.8) | 71 (12.8) | < 0.001 |
Fall within 1 year | 1270 (7.2) | 604 (6.9) | 484 (7.2) | 124 (8.0) | 58 (10.5) | 0.006 |
Study endpoints
Event | < 6.0% (n = 8725) | 6.0% to < 7.0% (n = 6700) | 7.0% to < 8.0% (n = 1548) | ≥ 8.0% (n = 553) | ||||
---|---|---|---|---|---|---|---|---|
Number of occurrences (%) | Incidence/100 person-years (95% CI) | Number of occurrences (%) | Incidence/100 person-years (95% CI) | Number of occurrences (%) | Incidence/100 person-years (95% CI) | Number of occurrences (%) | Incidence/100 person-years (95% CI) | |
Stroke/SEE | 247 (2.83) | 1.53 (1.34–1.72) | 218 (3.25) | 1.76 (1.52–1.99) | 50 (3.23) | 1.74 (1.26–2.23) | 25 (4.52) | 2.50 (1.52–3.49) |
Major bleeding | 181 (2.07) | 1.11 (0.95–1.28) | 130 (1.94) | 1.04 (0.86–1.22) | 30 (1.94) | 1.04 (0.67–1.42) | 12 (2.17) | 1.18 (0.51–1.85) |
ICH | 119 (1.36) | 0.73 (0.60–0.86) | 94 (1.40) | 0.75 (0.60–0.90) | 17 (1.10) | 0.59 (0.31–0.87) | 10 (1.81) | 0.98 (0.37–1.59) |
Cardiovascular death | 41 (0.47) | 0.25 (0.17–0.33) | 23 (0.34) | 0.18 (0.11–0.26) | 4 (0.26) | 0.14 (0.00–0.27) | 4 (0.72) | 0.39 (0.01–0.78) |
All-cause death | 568 (6.51) | 3.47 (3.18–3.75) | 450 (6.72) | 3.58 (3.25–3.91) | 98 (6.33) | 3.38 (2.71–4.05) | 58 (10.49) | 5.69 (4.23–7.16) |
Net clinical outcome† | 840 (9.63) | 5.21 (4.86–5.56) | 675 (10.07) | 5.47 (5.06–5.89) | 154 (9.95) | 5.40 (4.55–6.26) | 78 (14.10) | 7.83 (6.09–9.57) |
Total | HbA1c, % | Interaction P-value†† | ||||
---|---|---|---|---|---|---|
< 6.0 (n = 8721) | 6.0 to < 7.0 (n = 6699) | 7.0 to < 8.0 (n = 1548) | ≥ 8.0 (n = 551) | |||
HR† (95% CI) | HR† (95% CI) | HR† (95% CI) | HR† (95% CI) | HR† (95% CI) | ||
Stroke/SEE
DOAC | 0.84 (0.69–1.02) | 0.97 (0.71–1.32) | 0.71 (0.53–0.95) | 0.77 (0.40–1.45) | 1.75 (0.63–4.87) | 0.377 |
No OAC | 1.17 (0.83–1.67) | 1.29 (0.79–2.11) | 1.30 (0.73–2.30) | 0.66 (0.14–3.05) | 1.10 (0.11–11.26) | |
Major bleeding
DOAC | 0.81 (0.64–1.03) | 1.05 (0.73–1.50) | 0.56 (0.39–0.82) | 0.96 (0.40–2.29) | 1.04 (0.27–4.00) | 0.406 |
No OAC | 0.78 (0.48–1.25) | 0.94 (0.49–1.80) | 0.67 (0.29–1.51) | 0.48 (0.06–4.10) | 4.14 (0.27–63.78) | |
ICH
DOAC | 0.76 (0.57–1.02) | 1.04 (0.66–1.62) | 0.55 (0.36–0.85) | 0.61 (0.19–1.95) | 0.74 (0.17–3.31) | 0.671 |
No OAC | 0.60 (0.32–1.13) | 0.81 (0.36–1.83) | 0.52 (0.18–1.52) | 0.00 (-, -) | 0.00 (-, -) | |
CV death
DOAC | 0.84 (0.67–1.07) | 0.79 (0.56–1.11) | 0.76 (0.52–1.11) | 0.83 (0.33–2.06) | 5.52 (1.03–29.62) | 0.420 |
No OAC | 1.50 (1.02–2.21) | 1.15 (0.67–1.97) | 2.02 (1.08–3.78) | 0.92 (0.10–8.20) | 19.06 (1.56–233.10) | |
All-cause death
DOAC | 0.87 (0.76–0.99) | 0.79 (0.66–0.96) | 0.91 (0.74–1.12) | 0.81 (0.52–1.28) | 1.49 (0.77–2.90) | 0.367 |
No OAC | 1.39 (1.12–1.73) | 1.39 (1.04–1.87) | 1.42 (0.97–2.06) | 0.63 (0.21–1.88) | 3.50 (1.14–10.74) | |
Net clinical outcome
DOAC | 0.87 (0.74–1.03) | 0.86 (0.77–0.96) | 0.80 (0.68–0.95) | 0.85 (0.59–1.22) | 1.69 (0.96–2.97) | 0.103 |
No OAC | 1.26 (1.05–1.52) | 1.31 (1.01–1.69) | 1.32 (0.96–1.81) | 0.56 (0.23–1.36) | 3.09 (1.13–8.42) |
Total† | HbA1c, % | Interaction P-value††† | ||||
---|---|---|---|---|---|---|
< 6.0 (n = 1259) | 6.0 to < 7.0 (n = 3837) | 7.0 to < 8.0 (n = 1456) | ≥ 8.0 (n = 531) | |||
HR† (95% CI) | HR†† (95% CI) | HR†† (95% CI) | HR†† (95% CI) | HR†† (95% CI) | ||
With oral antidiabetic drugs (n = 4740), reference: no oral antidiabetic drug use (n = 3993)
| ||||||
Stroke/SEE | 0.99 (0.77–1.28) | 1.18 (0.60–2.31) | 0.84 (0.59–1.19) | 1.83 (0.78–4.29) | 1.36 (0.43–4.27) | 0.547 |
Major bleeding | 1.14 (0.84–1.56) | 1.54 (0.61–3.93) | 1.01 (0.64–1.60) | 0.71 (0.30–1.68) | 4.41 (0.49–40.17) | 0.470 |
ICH | 1.06 (0.73–1.55) | 1.90 (0.55–6.50) | 0.72 (0.42–1.21) | 0.71 (0.21–2.41) | NC†††† | 0.343 |
CV death | 0.96 (0.70–1.32) | 1.72 (0.69–4.28) | 0.68 (0.44–1.06) | 1.84 (0.58–5.84) | 4.88 (0.42–56.31) | 0.120 |
All-cause death | 0.91 (0.77–1.08) | 0.95 (0.61–1.48) | 0.78 (0.61–1.00) | 0.76 (0.47–1.23) | 1.46 (0.69–3.09) | 0.078 |
Net clinical outcome | 0.96 (0.83–1.10) | 1.07 (0.74–1.54) | 0.82 (0.67–1.00) | 0.88 (0.59–1.30) | 1.50 (0.79–2.84) | 0.108 |
With injectable antidiabetic drugs (n = 678), reference: no injectable antidiabetic drug use (n = 8055)
| ||||||
Stroke/SEE | 0.80 (0.50–1.28) | 1.16 (0.15–9.04) | 0.48 (0.15–1.52) | 1.09 (0.47–2.51) | 0.64 (0.24–1.72) | 0.840 |
Major bleeding | 0.86 (0.48–1.55) | NC†††† | 1.36 (0.54–3.42) | 0.95 (0.31–2.90) | 0.06 (0.00–0.72) | 0.546 |
ICH | 0.67 (0.30–1.46) | NC†††† | 1.11 (0.34–3.61) | NC†††† | 0.05 (0.00–1.44) | 0.596 |
CV death | 0.58 (0.31–1.10) | NC†††† | 0.44 (0.11–1.80) | 0.71 (0.20–2.58) | 0.55 (0.11–2.72) | 0.973 |
All-cause death | 1.02 (0.77–1.36) | 0.74 (0.18–3.08) | 1.31 (0.79–2.15) | 1.31 (0.77–2.22) | 1.04 (0.56–1.93) | 0.419 |
Net clinical outcome | 1.03 (0.81–1.30) | 0.71 (0.22–2.26) | 1.20 (0.78–1.84) | 1.31 (0.86–1.99) | 0.87 (0.51–1.47) | 0.449 |